Systemic lupus erythematosus (SLE) is a complex autoimmune disorder affect primarily and with wore severe manifestation in minority groups. Autoantibody production to multiple cellular antigens is a hallmark of this disorder. Although there is a considerable amount of clinical and experimental data indicating that some of these antibodies play a significant pathogenetic role, the origin of these autoantibodies and the complexity of their reactivities remain to be elucidated, representing a major focus of intense investigation of this disorder. In order to define carefully the clinical course and factors affecting the outcomes of this illness, the John Hopkins Lupus Cohort was established in 1989. The Cohort was enrolled over 450 patients with a database and a serum bank for storing serial sera. The careful quarterly clinical assessments and laboratory tests have yielded significant insights into the morbidity and mortality factors of this disease. Recently, autoantibody diversification has been shown in part due to epitope spreading, a process involving specific intra- and intermolecular determinants. Cross-reactive conformational epitopes shared my many autoantigens are partly responsible for this process. The investigators at the University of Virginia have developed a new antigen-induced SLE murine model and many of the preliminary findings are similar to the laboratory findings in patients. The proposal is to study SLE patients longitudinally to determine whether autoantibody diversification by epitope spreading occur in patients manifested by specific patterns and whether the emergence of new autoantibody specificities correlate with occurrence of new end organ damage. Specific emphasis is on the development of new kidney and skin involvement and thrombosis. Whether these new specificities have clinical predictive value will be ascertained. The effects of hydroxychloroquine on epitope spreading will be studied. To facilitate this approach a consortium between University of Virginia and John Hopkins Hospital is formed. The results of this inter-institutional collaborative project will have profound clinical implications in both our understanding of SLE pathogenesis and therapeutic approaches.